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Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance
- Source :
- Nature genetics, 49(1), 17-26. Nature Publishing Group, Nature Genetics, Vol. 49, No 1 (2017) pp. 17-26, Nature Genetics, 49(1), 17. Nature Publishing Group, Nature genetics, vol 49, iss 1, Lotta, L A, Gulati, P, Day, F R, Payne, F, Ongen, H, van de Bunt, M, Gaulton, K J, Eicher, J D, Sharp, S J, Luan, J, De Lucia Rolfe, E, Stewart, I D, Wheeler, E, Willems, S M, Adams, C, Yaghootkar, H, Forouhi, N G, Khaw, K-T, Johnson, A D, Semple, R K, Frayling, T, Perry, J R B, Dermitzakis, E, McCarthy, M I, Barroso, I, Wareham, N J, Savage, D B, Langenberg, C, O'Rahilly, S, Scott, R A & EPIC-InterAct Consortium (Kim Overvad; member) 2017, ' Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance ', Nature Genetics, vol. 49, no. 1, pp. 17-26 . https://doi.org/10.1038/ng.3714, Lotta, L A, Gulati, P, Day, F R, Payne, F, Ongen, H, Van De Bunt, M, Gaulton, K J, Eicher, J D, Sharp, S J, Luan, J, De Lucia Rolfe, E, Stewart, I D, Wheeler, E, Willems, S M, Adams, C, Yaghootkar, H, Forouhi, N G, Kerrison, N D, Sims, M, Lucarelli, D M E, Deloukas, P, McCarthy, M I, Arriola, L, Balkau, B, Barricarte, A, Boeing, H, Franks, P W, Gonzalez, C, Grioni, S, Kaaks, R, Key, T J, Navarro, C, Nilsson, P M, Overvad, K, Palli, D, Panico, S, Quirós, J R, Rolandsson, O, Sacerdote, C, Salamanca-Fernández, E, Slimani, N, Tjonneland, A, Tumino, R, Spijkerman, A M W, Van Der A, D L, Van Der Schouw, Y T, Riboli, E, Semple, R, Stears, A, George, S, Walker, M, Gurnell, E, Maguire, D, Mukhtar, R, Nag, S, Adler, A, Soeters, M R, Laji, K, Watt, A, Aylwin, S, Rayman, G, Hanna, F, Ellard, S, Ross, R, Blaslov, K, Duvnjak, L S, Khaw, K T, Johnson, A D, Frayling, T, Perry, J R B, Dermitzakis, E, Barroso, I, Wareham, N J, Savage, D B, Langenberg, C, O'Rahilly, S & Scott, R A 2016, ' Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance ', Nature Genetics, vol. 49, no. 1, pp. 17-26 . https://doi.org/10.1038/ng.3714
- Publication Year :
- 2016
-
Abstract
- Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.
- Subjects :
- 0301 basic medicine
Blood Glucose
Male
Adipose tissue
Genome-wide association study
Medical and Health Sciences
Body Mass Index
Pathogenesis
chemistry.chemical_compound
Mice
0302 clinical medicine
Adipocyte
2.1 Biological and endogenous factors
Insulin
Cambridge FPLD1 Consortium
ddc:576.5
Aetiology
health care economics and organizations
Adiposity
Diabetes
11 Medical And Health Sciences
Fasting
Genomics
Biological Sciences
Phenotype
Adipose Tissue
Cardiovascular Diseases
Medical genetics
epidemiology
Female
EPIC-InterAct Consortium
medicine.medical_specialty
030209 endocrinology & metabolism
Biology
Article
03 medical and health sciences
Insulin resistance
Metabolic Diseases
Clinical Research
Internal medicine
medicine
Genetics
Journal Article
metabolic disorders
Animals
Humans
Comparative Study
Obesity
Metabolic and endocrine
Triglycerides
Integrative genomic analysis, peripheral adipose storage capacity, human insulin resistance
Animal
Human Genome
Cholesterol, HDL
population genetics
06 Biological Sciences
medicine.disease
Familial partial lipodystrophy
Disease Models, Animal
030104 developmental biology
Endocrinology
chemistry
Diabetes Mellitus, Type 2
Genetic Loci
Case-Control Studies
Disease Models
Insulin Resistance
Developmental Biology
Genome-Wide Association Study
Subjects
Details
- Language :
- English
- ISSN :
- 10614036
- Database :
- OpenAIRE
- Journal :
- Nature genetics, 49(1), 17-26. Nature Publishing Group, Nature Genetics, Vol. 49, No 1 (2017) pp. 17-26, Nature Genetics, 49(1), 17. Nature Publishing Group, Nature genetics, vol 49, iss 1, Lotta, L A, Gulati, P, Day, F R, Payne, F, Ongen, H, van de Bunt, M, Gaulton, K J, Eicher, J D, Sharp, S J, Luan, J, De Lucia Rolfe, E, Stewart, I D, Wheeler, E, Willems, S M, Adams, C, Yaghootkar, H, Forouhi, N G, Khaw, K-T, Johnson, A D, Semple, R K, Frayling, T, Perry, J R B, Dermitzakis, E, McCarthy, M I, Barroso, I, Wareham, N J, Savage, D B, Langenberg, C, O'Rahilly, S, Scott, R A & EPIC-InterAct Consortium (Kim Overvad; member) 2017, ' Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance ', Nature Genetics, vol. 49, no. 1, pp. 17-26 . https://doi.org/10.1038/ng.3714, Lotta, L A, Gulati, P, Day, F R, Payne, F, Ongen, H, Van De Bunt, M, Gaulton, K J, Eicher, J D, Sharp, S J, Luan, J, De Lucia Rolfe, E, Stewart, I D, Wheeler, E, Willems, S M, Adams, C, Yaghootkar, H, Forouhi, N G, Kerrison, N D, Sims, M, Lucarelli, D M E, Deloukas, P, McCarthy, M I, Arriola, L, Balkau, B, Barricarte, A, Boeing, H, Franks, P W, Gonzalez, C, Grioni, S, Kaaks, R, Key, T J, Navarro, C, Nilsson, P M, Overvad, K, Palli, D, Panico, S, Quirós, J R, Rolandsson, O, Sacerdote, C, Salamanca-Fernández, E, Slimani, N, Tjonneland, A, Tumino, R, Spijkerman, A M W, Van Der A, D L, Van Der Schouw, Y T, Riboli, E, Semple, R, Stears, A, George, S, Walker, M, Gurnell, E, Maguire, D, Mukhtar, R, Nag, S, Adler, A, Soeters, M R, Laji, K, Watt, A, Aylwin, S, Rayman, G, Hanna, F, Ellard, S, Ross, R, Blaslov, K, Duvnjak, L S, Khaw, K T, Johnson, A D, Frayling, T, Perry, J R B, Dermitzakis, E, Barroso, I, Wareham, N J, Savage, D B, Langenberg, C, O'Rahilly, S & Scott, R A 2016, ' Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance ', Nature Genetics, vol. 49, no. 1, pp. 17-26 . https://doi.org/10.1038/ng.3714
- Accession number :
- edsair.doi.dedup.....61f062114ef776280f6ba26a09d47e80